Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features

• Published in: Nature communications Vol. 13; no. 1; p. 7551
• Main Authors: Flanagan, Dustin J., Amirkhah, Raheleh, Vincent, David F., Gunduz, Nuray, Gentaz, Pauline, Cammareri, Patrizia, McCooey, Aoife J., McCorry, Amy M. B., Fisher, Natalie C., Davis, Hayley L., Ridgway, Rachel A., Lohuis, Jeroen, Leach, Joshua D. G., Jackstadt, Rene, Gilroy, Kathryn, Mariella, Elisa, Nixon, Colin, Clark, William, Hedley, Ann, Markert, Elke K., Strathdee, Douglas, Bartholin, Laurent, Redmond, Keara L., Kerr, Emma M., Longley, Daniel B., Ginty, Fiona, Cho, Sanghee, Coleman, Helen G., Loughrey, Maurice B., Bardelli, Alberto, Maughan, Timothy S., Campbell, Andrew D., Lawler, Mark, Leedham, Simon J., Barry, Simon T., Inman, Gareth J., van Rheenen, Jacco, Dunne, Philip D., Sansom, Owen J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.12.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 14/19; 38/23; 38/61; 38/91; 45; 631/67/1059/602; 631/67/1504/1885/1393; 631/67/70; 64/110; 96/1; 96/100; 96/106; 96/2; 96/95; Adenomatous polyposis coli; Apoptosis; Apoptosis - genetics; Cancer; Colorectal cancer; Colorectal carcinoma; Epidermal growth factor receptors; Epithelial cells; Epithelium; Humanities and Social Sciences; Humans; Inhibitors; MAP kinase; multidisciplinary; Mutation; Science; Science (multidisciplinary); Signaling; Transforming Growth Factor beta; Tumorigenesis; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35134-3

The pro-tumourigenic role of epithelial TGFβ signalling in colorectal cancer (CRC) is controversial. Here, we identify a cohort of born to be bad early-stage (T1) colorectal tumours, with aggressive features and a propensity to disseminate early, that are characterised by high epithelial cell-intrinsic TGFβ signalling. In the presence of concurrent Apc and Kras mutations, activation of epithelial TGFβ signalling rampantly accelerates tumourigenesis and share transcriptional signatures with those of the born to be bad T1 human tumours and predicts recurrence in stage II CRC. Mechanistically, epithelial TGFβ signalling induces a growth-promoting EGFR-signalling module that synergises with mutant APC and KRAS to drive MAPK signalling that re-sensitise tumour cells to MEK and/or EGFR inhibitors. Together, we identify epithelial TGFβ signalling both as a determinant of early dissemination and a potential therapeutic vulnerability of CRC’s with born to be bad traits. It remains critical to identify colorectal cancers (CRC) that will disseminate as early as possible. Here, the authors identify CRC tumours that are aggressive and prone to early dissemination, characterised by epithelial TGFβ and growth-factor signalling - which could be targeted with MEK/EGFR inhibitors.